Alzheimer's disease (AD) is the most common cause of irreversible, chronic dementia. Although AD may be familial in only one-third of all cases, the main justification for studying autosomal dominant cases lies in the accuracy of diagnosis which may be inferred through post-mortem examination of other affected family members. More than 250 members of 20 pedigrees with an autosomal dominant form of AD have had skin fibroblast and peripheral blood lymphoblast cultures established. These cultures serve as a renewable source of DNA and cell lines for genetic linkage, viability, and bIochemical studies. Recombinant DNA technology has been applied to perform genetic linkage studies in these families with inherited AD. Additional families have provided further confirmation of our earlier finding of a region of chromosome 21 that is linked to AD in early onset cases; however, a single marker has not been identified. In a collaborative study of 70 families, the age-at-onset showed a bimodal distribution. The lifetime AD risk for at-risk offspring in early onset cases was 53%, significantly lower than 86% in late onset AD. Transmission pattern and age-at-onset provide further evidence for heterogeneity. Longitudinal investigation of neurotransmitters/neuropeptides in cerebrospinal fluid (CSF) continues to confirm our previous findings; three at-risk subjects, among the subgroups with low CSF MHPG and somatostatin, have developed dementia. Anti-neuronal antibodies have also been detected in the CSF from AD patents. These antibodies recognize specific neuronal populations in the adult rat central nervous system. In developing rat brain these antibodies recognize specific membrane receptors in macrophagic microglia. Inflammation and similar immune mechanisms may play a pathogenetic role in AD. Cerebral glucose metabolism is significantly reduced in the parietotemporal regions with some occipital and temporal involvement. A mild (10-17%) reduction was observed in three at-risk subjects who later developed AD.